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The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 microM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 microM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 microM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity. Copyright 2003 Lippincott Williams & Wilkins

Citation

Byung Ho Lee, Chong Ock Lee, Myung-Ja Kwon, Kyu Yang Yi, Sung-Eun Yoo, Sang-Un Choi. Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity. Anti-cancer drugs. 2003 Feb;14(2):175-81

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PMID: 12569305

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